Dr.Anitha. M Associate Professor S A T Hospital Trivandrum OVULATION INDUCTION Dr.Anitha. M Associate Professor S A T Hospital Trivandrum

Ovarian stimulation aims at the development of one or more ovarian follicles to reach the stage of maturity culminating in the release of one or more mature oocytes ready for fertilization. Ovulation Induction – mono ovulation. Controlled Ovarian Hyperstimulation – multifollicular development.

What are the objectives of ovulation induction? To induce monofollicular development and ovulation in anovulatory infertile women To augment ovulation in unexplained infertility For controlled ovarian hyperstimulation (COH) in IUI and ART

Mono follicular ovulation Duration of FSH secretion limited by negative feedback from estrogen produced by larger follicles Smaller follicles with fewer FSH receptors no longer stimulated to grow by decreasing FSH levels undergo atresia Therefore a single follicle reaches maturation stage FSH estrogen atresia mature follicle Mono follicular ovulation negative feedback reduced stimulation 4

FSH stimulates granulosa cell proliferation and aromatase production LH stimulates androstenedione production by theca cells that diffuses into granulosa cells Aromatase converts androstenedione into estrogen granulosa cells FSH aromatase estrogen LH theca cells androstenedione 5

Prevalence of PCOS Polycystic ovaries are present in 5-7% of women worldwide. PCOS with anovulation constitute 60-85% of WHO group II women who would benefit from OI therapy

Life style interventions Important in WHO 2 group –anovulatory. Insulin resistance Hyperandrogenism Clinical Biochemical Obesity- 50% of PCOS have BMI >25 kg/m2 ↑ miscarriage Congenital abnormalities Gestational diabetes / PIH Still birth Maternal mortality Long term effects – DM , CVD

Benefits of weight reduction Normalises endocrine mileu Improvement of insulin sensitivity & hyperandrogenism. Return of regular spontaneous ovulation Pregnancy

All obese women with a BMI > 35 kg/m2 , seeking pregnancy should be denied any form of fertility treatment , until limited- at least 5 -10 % weight reduction has been achieved. Stop smoking – depletes follicles. Diet restriction – reduction of glycaemic load Exercise.

Mechanism of Ovarian Stimulation Pharmacological agents. Moderate and manipulate endogenous gonadotropins. Oral agents. Selective Oestrogen receptor modulators –SERMS. Clomiphene citrate, Tamoxifen. Modulate oestrogen production – Aromatase inhibitors. Letrozole , Anastrazole. Injectables. Gonadotropins

Clomiphene citrate First line drug for most anovulatory or oligo-ovulatory infertile women with adequate estrogen (WHO type II esp PCOS) and a positive progesterone challenge test Not for women with low E levels (WHO type I and III women)

Clomiphene Citrate Greenblatt in 1962. Long half life 5-21 days. Stored in body fats. Estrogen agonist and antagonist –SERM. Agonist properties manifest only when endogenous oestrogen levels are very low. Racemic mix of enclomiphene and Zuclomiphene.

Enclomiphene more potent antioestrogenic Responsible for the ovulation stimulation Half life of few days. Zuclomiphene cleared more slowly. Responsible for the peripheral action.

1 2 3 4 5 CC binds to ER and depletes receptor concentrations Hypothalamus Pituitary estrogen –ve feedback interrupted 2 3 FSH stimulation continues More smaller follicles are rescued 4 Multiple follicles develop 5

Mechanism of action Binds to estrogen receptors. Bindings lasts upto weeks. Depletes estrogen receptors. Main site is hypothalamus, also the pituitary. ER depletion interpreted as low levels. Reduced negative feed back. GnRH ↑, FSH /LH ↑ So intact HT-Pituitary axis & endogenous E must

Why the peripheral antiestrogenic effects? Prolonged ER depletion CC has a long half-life of days upto 7 weeks. Prolonged ER depletion This results in prolonged increase of FSH Supraphysiological levels of E All this causes the antiestrogenic effects in the endometrium Extension of the FSH window leads to multiple ovulation and increased multiple pregnancy

Dosage 50 mg daily D 2 – D 5. Increments of 50 mg. Dose ranging from 50 – 250 mg/day. No indication to further ↑dose ,once ovulation achieved. Higher doses do not improve pregnancy rates. Failure to respond to 150 mg will require alternative treatments. Pregnancy rates increased in the first 3 cycles. Beyond 6 cycles , not recommended. (BFS) / 12 m (RCOG)

Results of accelerated dose and extended dose has not been found to be effective.

Follicular monitoring Baseline scan on day 2 Start monitoring on day 7 – 10 Pre ovulatory follicle 17 to 25 mm Endometrial thickness at least 7 mm triple line appearance

Efficacy of Clomiphene Clomiphene induces ovulation in 60-80% of well selected cases More than 70% will ovulate at the 50 -100 mg doses However, pregnancy rate is only 20- 40% Pregnancy rate / cycle is a mere 10-20% Failure to conceive within 6 months of ovulatory cycles should warrant other investigations

Drawbacks of clomiphene pituitary/hypothalamus Induces ovulation Anti-Estrogenic effects contributing to reduced pregnancy rates clomiphene Endometrial thickness < 5-6 mm Reduction in glandular density Increase in number of vacuolated cells Decreased uterine blood flow during early luteal phase isomers endometrium cervical mucus Change in quantity or quality of mucus Miscarriage rate of 26% 22

Clomiphene – side effects Multiple pregnancy 3% - 13% Hyperstimulation 6% Vasomotor flushes Visual symptoms like blurring of vision Breast tenderness Persistence of follicular cysts Abdominal discomfort

Question of whether treatment with ovulation induction drugs increases risk of ovarian tumours or cancer remains unsettled,but cannot be summarily dismissed. Women who are offered ovulation induction should be informed that a possible association between ovulation induction therapy and ovarian cancer remains uncertain. Practitioners should confine the use of ovulation induction agents to the lowest effective dose and duration of use. Nice Fertility Guidelines; 2004

Adjuvants to clomiphene Metformin Bromocriptine or cabergoline in assoc hyperprolactinaemia Thyroxine in assoc hypothyroidism Dexona in the rare case of increased DHEAS levels HCG for the LH surge

Clomiphene resistance & failures CC resistance (CRA) Failure to ovulate Insulin resistance Inappropriate indication About 20-25% of anovulatory women are CC resistant CC failures (CCF) Ovulate , but fail to get pregnant Underlying other factors ? Antioestrogenic effects 26

Clomiphene resistance – how to manage? CC+ gonadotrophins Gonadotrophins Lap ovarian puncture

Aromatase Inhibitors. Aromatase enzyme catalyses the rate limiting step- the conversion of androgens to oestrogens.

Role of aromatase Brain Adipose tissue Muscle Liver Breast tissue Ovaries Brain Adipose tissue Muscle Liver Breast tissue Malignant breast cancers androstenedione estrone aromatase testosterone estradiol Casper RF and Mitwally M, et al. Review: Aromatase inhibitors for ovulation induction. J Clin Endocrinol Metab, 2006; 91: 760-771 29

Pharmacokinetics Rapidly absorbed bioavailability 99.9% Widely dist in all tissues esp brain Metabolised and eliminated in liver rapidly Half life is very short (about 50 hours)

3 4 5 2 1 6 Comp and reversibly binds to haem subunit of aromatase Inhibits aromatase in ovaries and peripheral tissues reducing estrogen levels Negative feed back being active stimulates hypothalamus-pituitary axis GnRH release produces FSH FSH-mediated stimulation of follicle Rising estrogen level from follicle suppresses FSH leaving a single dominant-follicle Normal FSH window Physiological levels of E 3 -ve feedback stimulation 4 Hypothalamus Pituitary GnRH released FSH stimulation 5 2 Falling FSH estrogen –ve feedback Smaller follicles undergo atresia 1 6 Single follicle develop androstenedione  estrogen aromatase inhibition 31

Peripheral actions Androgen accumulate in follicle stimulates FSH receptors and IGF-1 which promote folliculogenesis. Low E levels results in up regulation of ER in the endometrium and increasing sensitivity to subsequent E and thereby normal endometrial development

Dose of letrozole Dosage is 2.5 -5 mg daily from day 3 for 5 days Side effects very mild (GIT related) and seldom necessitate discontinuation

Clomiphene & Letrozole Long half life Mechanism is receptor blockade Antiestrogenic effects Supraphysiological levels of E detrimental to embryos Receptors are depleted in the endometrium and so poor endometrial response may impair implantation More chance of miscarriage Short half life (only 2 days) Mechanism is aromatase inhibition No such effects Physiological levels of E No effect on receptors ER are upregulated and endo response is good Less chance

Letrozole along with gonadotrophins in COH

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Letrozole plus gonadotrophins Significant reduction in FSH dose Less antiestrogenic effects compared with clomiphene Pregnancy rates equivalent to FSH alone and twice that with FSH and clomiphene Marked reduction in cost May improve response to FSH in poor responders

What is the place of aromatase inhibitors? Ovulation induction in clomiphene resistance and failures in PCOS and unexplained infertility As an alternative to clomiphene Along with FSH for COH for IUI In poor responders of FSH ART?

Ovarian stimulation by aromatase inhibitors is associated with significantly lower oestrogen production per follicle, hence overall lower E levels. Certain groups are definitely benefitted by this Women with oestrogen dependent disorders like endometriosis or breast cancer, or those with inherent clotting abnormality.

Gonadotropins CRA / CCF HMG / HP HMG / Recombinant FSH Direct stimulation of the follicular growth. Step up / Step down protocol Strict cancellation criteria - >3 follicles 12 mm Ovulation 82% Pregnancy 58% Multiple pregnancy 11 – 44%

Gonadotrophins Close monitoring Usually step up protocols Start with lowest dose in PCOS TVS from day 7 and increased dose acc Problems Multiple pregnancy 20% OHSS Premature LH surge

Insulin sensitizers Metformin – Biguanide Restores endocrine mileu Lowers insulin resistance Lowers hyperandrogenism Normalises ovarian response to FSH Dose – 500 mg 2-3 times daily Not a first line drug / combination with CC not superior. Second line in patients with CRA and BMI >35 and IGT (ESHRE & ASRM) Not licensed for OI GI side effects – nausea , vomiting , diarrhea.

LEO In CRA Drilling small holes in the ovarian cortex – drains androgen rich fluid Cumulative pregnancy rate, live birth rate , abortion rate comparable with gonadotropins Multiple pregnancy rates lowered significantly. Risk of surgery, accelerated decline of ovarian reserve.

To take home….. In chronic anovulation, life style modification may be the first step. Important to distinguish between WHO Type 1 and 2 anovulation. Follow the traditional sequence for OI – CC followed by exogenous FSH. Frequent monitoring and strict cancellation criteria will prevent serious complications like high order pregnancy and OHSS. Enhancement of local circumstances,aiming to reduce hyperinsulinaemia and hyperandrogenism

CC for not more than 6 cycles. Start with lowest dose , accelerate only when required. Gonadotropins in CRA / CCF / COH . Ovulation induction to be restricted to patients presenting with infertility and chronic anovulation and it should primarily aim at restoring physiology.

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